In 1942 Albright described the features of an inherited clinical syndrome named "pseudohypoparathyroidism" (PHP). The biochemical hallmark of PHP is a lack of response of urinary cyclic AMP (cAMP) to exogenous parathyroid hormone (PTH). This indicates that there is a defective hormone receptor- adenylyl cyclase complex in this disorder. Patients with one form of PHP show characteristic constitutional features (Albright's hereditary osteodystrophy - AHO) and resistance to multiple hormones including PTH, thyrotropin and gonadotropins (PHP Ia). Other affected relatives from PHP Ia kindreds have AHO without hormone resistance (pseudopseudo- hypoparathyroidism, PPHP). We have shown that many patients with PHP Ia and PPHP show an approximately 50% reduction in activity of Gs (the stimulatory guanine nucleotide binding protein associated with adenylyl cyclase) in membranes from multiple tissues. We have shown that steady state Gs-alpha mRNA levels from fibroblasts of subjects with PHP Ia and PPHP are reduced by approximately 50% compared with normals and have identified genetic abnormalities which account for Gs deficiency. It has recently been suggested that the same genetic defect in the Gs-alpha gene may result in PHP Ia or PPHP by a mechanism called parental imprinting. Another form of PHP is characterized by isolated PTH resistance without features of AHO or resistance to other hormones (PHP Ib). Previous work in this laboratory showed a selective resistance of cAMP generation to PTH in fibroblasts from these patients, suggesting a potential defect in the PTH receptor. Molecular studies to date suggest that these are not due to mutations in the coding exons of the PTH receptor gene. There are also a small number of patients who have AHO and generalized hormone resistance but who do not have a Gs defect (PHP Ic). The molecular defect in these patients have not as yet been identified.